The overall goal of this Program Project Grant is to understand how peroxisomal disorders disturb cell function and cause mental retardation, with the ultimate objective of providing therapy for these devastating disorders. At least 15 genetically determined peroxisomal disorders have been identified, 12 of which are associated with mental retardation. The gene defects in 4 of these disorders, including that in X-linked adrenoleukodystrophy (X-ALD) have been defined in the last 3 years; others are likely to be defined in the near future. The phenotypes of X-linked ALD, as well as the disorders of peroxisome assembly which have been subdivided into 11 complementation groups, show wide and unexplained variability which has hampered classification and evaluation of therapy. Aim 1 will reexamine phenotypes and their natural history in large groups of patients, in the light of the new knowledge gained about their molecular biology. Aim 2 will develop diagnostic assays that can be applied to blood spots on filter paper and use these to determine the frequency of these disorders. This method will also be applied to screen mutant mice at the Jackson laboratory in order to seek animal models. Aim 3 is designed to identify the genetic causes of phenotypic variability of X-ALD by a) seeking a putative modifier gene and b) comparing immunological phenomena and apoptosis in the severe childhood cerebral form with the milder adrenomyeloneuropathy form. A key role of this project is to provide samples from carefully classified patients for basic studies of cell biology and pathogenesis to aid the design and evaluation of new forms of therapy.